7avq | pdb_00007avq

Crystal structure of haspin in complex with disubstituted imidazo[1,2- b]pyridazine inhibitor (compound 12)

spinqualitylabelsall models 7avq, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7avq is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MPD, NA, S1Z Gene: HASPIN, GSG2 (HUMAN) Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HASP_HUMAN] Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle. Publication Abstract from PubMed Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB. Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.,Elie J, Feizbakhsh O, Desban N, Josselin B, Baratte B, Bescond A, Duez J, Fant X, Bach S, Marie D, Place M, Ben Salah S, Chartier A, Berteina-Raboin S, Chaikuad A, Knapp S, Carles F, Bonnet P, Buron F, Routier S, Ruchaud S J Enzyme Inhib Med Chem. 2020 Dec;35(1):1840-1853. doi:, 10.1080/14756366.2020.1825408. PMID:33040634 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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